Daratumumab monotherapy for relapsed <scp>POEMS</scp> syndrome
Authors: Danai Dima, Jason Valent, Jack Khouri
Journal: American Journal of Hematology (2023)

POEMS (Polyneuropathy, Organomegaly, Endocrinopathies, Monoclonal protein, Skin changes) syndrome is a rare paraneoplastic manifestation related to an underlying plasma cell neoplasm. It is a heterogeneous disease with a variety of signs and symptoms affecting multiple organ systems.1 The underlying pathogenesis is complex and not well understood; however, VEGF levels correlate with disease activity. POEMS diagnosis is challenging and often delayed due to misdiagnosis. It requires the presence of both mandatory criteria (neuropathy and monoclonal protein), at least one major criterion (elevated VEGF, sclerotic bone lesions, and Castleman disease), and at least one minor criterion (volume overload, endocrinopathy, organomegaly, thrombocytosis/polycythemia).1 There is no consensus on how to treat POEMS due to lack of large randomized clinical trials given the rare nature of the disease. To date, most experience and treatment practices are based on retrospective studies and case reports.2-4 Therapy mainly focuses on eradicating the underlying plasma cell clone and implements plasma cell-directed agents used in multiple myeloma (MM).5 Radiation can be used if there are a limited number of bone lesions, while systemic therapy is recommended if there are widespread bone lesions and/or bone marrow involvement. Lenalidomide-based regimens and autologous hematopoietic cell transplant (AHCT) are widely used as first-line strategies. A small (n = 25), randomized phase II/III trial has previously assessed the use of thalidomide-dexamethasone in POEMS patients ineligible for AHCT and showed a significant reduction in serum VEGF levels compared to placebo.6 Another phase II study (n = 41) of lenalidomide-dexamethasone demonstrated high hematologic, VEGF, and clinical responses in naïve POEMS patients, with impressive 3-year progression-free and overall survival rates of 75% and 90%, respectively.7 However, POEMS is an incurable disease with a significant percentage of patients relapsing or having persistent symptoms requiring further therapy. Daratumumab (dara) is an anti-CD38 monoclonal antibody approved for MM and light-chain amyloidosis with remarkable activity. To date, limited reports have described the use of dara in POEMS syndrome. Herein, we present a case series describing our experience using dara monotherapy in patients with relapsed POEMS. We identified seven patients with relapsed POEMS who were treated with single-agent dara between January 2017 and January 2023 at Cleveland Clinic (CCF). The study was approved by the CCF Institutional Review Board, which granted a waiver of consent. Data were extracted from electronic medical records by trained abstractors. Hematologic responses were assessed according to the criteria by Dispenzieri et al.1 and included complete response (CRH), very good partial response (VGPRH), partial response (PRH), and no response (NRH). Overall hematologic response rate (ORRH) was defined as ≥PRH. CRH was defined as negative serum immunofixation and absence of clonal plasma cells in the bone marrow. VGPRH was defined as ≥90% reduction of monoclonal (M)-protein or positive immunofixation (given baseline M-protein of at least 0.5 g/dL). PRH was defined as ≥50% reduction in M-protein (given baseline M-protein of at least 1 g/dL). NRH was defined as not meeting criteria for CRH, VGPRH, or PRH. Likewise, VEGF responses (baseline must be ≥200 pg/mL) included: CRV (normalization of plasma VEGF <87 pg/mL), PRV (decrease of VEGF ≥50%), and NRV (less than PR). Clinical responses were as follows: CRC (total resolution of symptoms), PRC (partial resolution of symptoms), and NRC (no improvement in symptoms). Progressive disease was defined as either hematologic progression (at least 25% increase of M-protein from the lowest level, which must be >0.5 g/dL), or plasma VEGF increase above >200 pg/mL, or clinical progression (attributable to disease only). Descriptive statistics were used. Kaplan–Meier method was applied for progression-free survival (PFS) and time-to-next treatment (TTNT) analyses using R software (version 3.6.2). The median age at POEMS diagnosis was 56 (range 47–75) years; 4 patients (57%) were female. Two patients (29%) were African American, and 1 (14%) was Hispanic. Three patients (43%) had radiographic sclerotic bone lesions, three (43%) had volume overload, three (43%) had organomegaly, and one (14%) had endocrinopathy. Four (57%) and two (29%) patients had IgG and IgA isotypes, respectively. Fluorescence in situ hybridization (FISH) analysis was reported in three patients at diagnosis, the rest four had insufficient plasma cells. One patient had normal FISH, and two patients had IgH translocations, one with t(11;14) and the other with t(14;16). None had deletion of chromosome 17p13 (TP53). The patient with the t(14;16) additionally had deletion of chromosome 13q. Baseline characteristics at diagnosis and at dara initiation are summarized in Table 1. Endocrinopathy (Hypogonadism and Adrenal Insufficiency) Frontline therapy included lenalidomide-dexamethasone (n = 3, 43%), cyclophosphamide-dexamethasone (n = 1, 14%), and cyclophosphamide-lenalidomide-dexamethasone (n = 3, 43%). None had received prior upfront or salvage AHCT. The median number of prior lines of therapies was 2 (range 2–3). The median age at dara initiation was 58 (range 54–79) years. The median time from diagnosis to dara initiation and median time on dara were 68 (IQR 54–78) and 14 (IQR 9–29) months, respectively. Median follow-up time was 28 (IQR 13–30) months from dara initiation. Dara was given either intravenously (n = 4, 57%) or subcutaneously (n = 3, 43%), per standard dosing schedule, until disease progression, except for two patients: one discontinued dara after 6 months of initiation per their preference, and the other discontinued dara after 29 months, given sustained benefit, per physician's discretion. Of the seven patients, five were evaluable for hematologic response. Hematologic ORR was 100%; two (40%) patients achieved VGPRH and three (60%) achieved PRH. Four out of the seven patients were evaluable for VEGF response; two (50%) achieved CRV, and the remaining two (50%) achieved PRV. Three patients were evaluable for both hematologic and VEGF responses, all of whom achieved dual responses. With regard to clinical response, one (14%) patient achieved CRC, five (72%) patients achieved PRC, and the remaining one (14%) patient had no symptomatic improvement, neuropathy in particular. Of the six patients who achieved clinical response, 83% had a hematologic response and 67% had a VEGF response. Single-agent dara led to durable remissions with the estimated median PFS not reached. The estimated median TTNT from date of dara initiation was also not reached. Two patients eventually progressed, four months and 29 months from dara initiation, respectively. The remaining patients did not progress throughout the duration of the study. Within 1 year, 86% of patients remained in remission. All patients were still alive at the data cutoff. None of the patients discontinued dara due to adverse events. In addition, no deaths occurred while on dara. Adverse events mainly included grade 2 infusion-related reactions in three (43%) patients, all during the first intravenous infusion of dara. One (14%) patient developed massive pulmonary embolism while on dara but this was felt to be unrelated to the monoclonal antibody. None of the patients developed significant infections while on dara. This is the largest retrospective case series on outcomes of patients with relapsed POEMS syndrome treated with dara monotherapy. Dara appears effective in achieving long-lasting responses with an overall benign adverse event profile. All patients responded to therapy on either a hematologic, VEGF and/or clinical level. Importantly, none discontinued therapy due to adverse events. In this case series, all patients except one had previously received lenalidomide-based therapy with or without cyclophosphamide, and all responded to dara therapy, which was given as 2nd or 3rd line of treatment. A prior case report highlighted that single-agent dara led to a deep hematologic response associated with clinical improvement in a patient who failed to respond to frontline lenalidomide-dexamethasone.8 A recent case series described three patients who were treated with dara-bortezomib-dexamethasone triplet post-AHCT, with good VEGF and clinical responses.9 Dara has also been utilized in the upfront setting in combination with lenalidomide-dexamethasone with high efficacy.10, 11 A prospective trial (NCT04396496) is currently enrolling to assess dara's safety and efficacy in combination with lenalidomide in POEMS syndrome, with results eagerly awaited. A retrospective analysis of 79 patients has previously described outcomes with the use of traditional plasma-cell-directed therapies in relapsed POEMS syndrome. Overall hematologic and VEGF responses were 56% and 31%, respectively.12 Novel therapies were used in a small percentage of patients; however, the exact description of novel agents was not outlined. Most recently, a study from the Mayo clinic reported that dara-based therapies yielded an overall response rate of 75% in 16 patients with POEMS syndrome.13 Dara was used with dexamethasone alone, or as part of a triplet (immunomodulatory drug [IMiD]-steroid or cyclophosphamide-steroid) or quadruplet regimen. Notably, duration of therapy in those treated with dara-IMiD-steroid triplets exceeded 2.5 years. However, in that study, only two patients were treated with dara-dexamethasone, with the authors concluding that little could be said for the value of this doublet due to their limited sample size. Based on our experience, dara yielded a 100% response rate (hematologic and/or VEGF to all the evaluable patients) and thus may constitute a very promising therapeutic option in the relapsed setting. Table 2 compares the results of the Mayo study to the current cohort. Apart from dara, other novel drug combinations, including carfilzomib with or without IMiD and steroid, also appeared safe and efficacious in the relapsed setting in the Mayo report.13 Our study has limitations, including its retrospective nature and the overall small sample size. In addition, the role of dara post-AHCT cannot be ascertained given that none of our patients had previously undergone AHCT, a common first-line strategy for POEMS patients who are AHCT-eligible. In conclusion, our results demonstrate encouraging outcomes with the use of single-agent dara in patients with relapsed POEMS syndrome. Prospective studies are needed to confirm our findings and provide further information with regard to efficacy and safety of dara as monotherapy or in combination with other agents in this rare disorder. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Danai Dima has no conflicts of interest to declare. Jack Khouri: Janssen (consulting). Jason Valent: Alexion, AstraZeneca Rare Disease (Research Funding). Due to privacy, ethical concerns, and institution policy supporting data cannot be made openly available.